Complement is paradoxically involved in two phenomena representing opposing consequences of interaction between tumor cells and host immune response in the mouse: escape of tumor cells from immune destruction in the presence of excess antibody to tumor cell antigens (antigenic modulation) and rapid lysis of spontaneously-arising leukemias following infusion of heparinized plasma from normal mice (plasma therapy of leukemia). Detailed analysis of thymus-leukemia (TL) antigen modulation in vitro has revealed that lysis of TL-antibody-sensitized cells is blocked by localized "microaggregation" of TL antigen-antibody complexes on the cell surface and intercalation of mouse C3 molecules into these aggregates. TL modulation in vivo appears to occur in similar fashion, with TL atibody being retained on leukemia cells and thymocytes for days and even weeks after modulation is completed. Modulation of H-2 antigens occurs in vitro on peritoneal cells, but not on thymocytes, lymphocytes, or leukemia cells; on peritoneal cells, the mechanism appears comparable to the mechanism underlying TL modulation. Analysis of AKR mouse serum for antibody reactive with autologous or syngeneic thymocytes or leukemia cells has revealed the presence of cytotoxic autoantibody and cytotoxic antibodies reactive with leukemia virus-infected cells. Antibody levels progressively increase with age and with leukemia development, and are paralleled by increased circulating immune complexes and decreased levels of C3-related serum-modulating factors active in TL modulation in vitro.